Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
  • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
  • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
  • A61K31/566—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol having an oxo group in position 17, e.g. estrone
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
  • A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
  • A61K35/22—Urine; Urinary tract, e.g. kidney or bladder; Intraglomerular mesangial cells; Renal mesenchymal cells; Adrenal gland
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07J—STEROIDS
  • C07J31/00—Normal steroids containing one or more sulfur atoms not belonging to a hetero ring
  • C07J31/006—Normal steroids containing one or more sulfur atoms not belonging to a hetero ring not covered by C07J31/003

Definitions

• estrone sulfate The sodium salt of estrone sulfate is well known to possess great importance as the principal component of the water soluble estrogens extracted from the urine of pregnant mares. It is also well known that sodium estrone sulfate, as present in preparations made from extracts of pregnant mares urine, remains stable and retains its water solubility under normal conditions of storage.
• a stable synthetic sodium estrone sulfate preparation can be obtained by mixing synthetic sodium estrone sulfate with an extract of pregnant mares urine.
• extract of pregnant mares urine refers to a water and alcohol soluble extract of pregnant mares urine ordinarily containing from about 1% to about 20% of natural conjugated estrogens. Numerous procedures for preparing such extracts are described in prior patents and literature, but they may be classified into two principal types. In one type, pregnant mares urine is extracted with a polar solvent, n-butanol being especially useful, and then the extract is subjected to various stages of purification which may increase the estrogen content. The other type is based on absorption of the estrogens onto an absorbent such as carbon and subsequent elution and purification.
• the purification ordinarily does not proceed beyond the point of increasing the estrogen content above about 20%, although extracts having a higher estrogen content up to about 30% may be employed if desired. It is especially preferred to utilize an extract of pregnant mares urine having a natural con- 3,644,618 Patented Feb. 22, 1972 jugated estrogen content within the range of about 5% to about 12%. However, either method of preparation of the extract may be used.
• EXAMPLE I.FLOW SHEET [Extract of pregnant mares urine] 5,046 gallons (22,707 litres) of pregnant mares urine. extract with .Ln-butanol.
• estrone 12049 g. (expressed as estrone) or 2,827 g. (expressed as sodium estrone sulfate evaporate in vacuo (50 0.).
• n-butanol 5046 gallons (22,707 litres) of pregnant mares urine was extracted with n-butanol, and the 13,313 litres of extract was Washed with 102.5 kg. of NaOH as a 2 N solution and 80.1 kg. of NaHCO as a saturated solution.
• the n-butanol extract was evaporated in vacuo at 50 C., water being added slowly to replace and allow for the removal of the butanol.
• the aqueous concentrate was diluted to 1200 litres, and washed with litres of ethylene dichloride. Following a careful adjustment of pH to 4.5 with concentrated HCl, the aqueous concentrate was washed with 120, 60 and 60 litres of ethylene dichloride.
• the pH was adjusted to greater than 7.5 by the addition of NaHCO (25.3 kg), and the aqueous concentrate extracted three times with n-butanol (total volume 1008 1.).
• the butanol extract was evaporated in vacuo, affording a concentrated extract (34.95 kg.) which was dissolved in methanol and filtered, affording a methanolic solution of the extract in which the natural con- *jugated estrogens constituted about 8% of the extract.
• EXAMPLE II 6229 gallons of pregnant mares urine were processed by substantially the same procedure as outlined in Example I. The 43.5 kg. of extract obtained assayed 7.8% and which represented 3.385 kg. of natural conjugated estrogens, expressed as sodium estrone sulfate, calculated by the OAAC assay.
• EXAMPLE III 28,274 gallons of pregnant mares urine were processed according to Examples I and II.
• the natural conjugated estrogens were 7% of the extract (AOAC Assay).
• EXAMPLE IV 20,300 gallons of pregnant mares urine were processed according to Examples I and II.
• the natural conjugated estrogens were 7.6% of the extract, the assay employed in this case being the AOAC.
• d Na equilin sulfate in mg./ g. separately determined colorimetrically against USP Reference Standard equilin after treatment of another with Fe-Kober reagent. This method will be referred to herein as the AOAC assay.
• a composition in accordance with the present invention comprises synthetic sodium estrone sulfate in admixture with an extract prepared from the urine of pregnant mares in which the natural conjugated estrogens constitute from about 1% to about 30% of said extract, and the synthetic sodium estrone sulfate constitutes from about to about 90% of the total estrogens in the mixture.
• the synthetic sodium estrone sulfate component of the mixture can vary from about 10% to about 90% of the total estrogen content, the preferred range is from about 40% to about 75%.
• said composition may also include additional therapeutic substances, e.g.
• pharmacologically-acceptable carriers such as tricalcium phosphate, calcium carbonate, magnesium carbonate, celite, silica gel, powdered cellulose, lactose, starch, sodium bicarbonate, and the like.
• EXAMPLE V A methanol solution of 1.887 g. of an extract prepared from the urine of pregnant mares was mixed With a methanol solution containing 0.663 g. of synthetic sodium estrone sulfate. The methanol was removed in vacuo at 40-50" C. to obtain a brown free-flowing hygroscopic powder.
• the stability of the synthetic sodium estrone sulfate in the powder, as compared with that of a control sample of the crystalline sodium estrone sulfate is shown by the table, due account in the assay being taken of. the natural estrogens present in the powder.
• a production batch totalling 108.72 kgs. of powder is made by mixing 95.75 kgs. of tricalcium phosphate with 26.594 litres of a methanolic solution of an extract of pregnant mares urine weighing 10.3 kgs., prepared according to the methods of Examples 1 to 4, containing as natural conjugated estrogens 37.966 mg./ml. (9.7%) and 48.7 litres of a methanolic solution of. synthetic sodium estrone sulfate containing 39.5 mg./ml. (66% of the total estrogens), and the preparation is dried in vacuo at 40 C. to remove the solvent and to afford a free flowing powder.
• a composition comprising unstable crystallive synthetic sodium estrone sulfate stabilized by admixture with a water and alcohol-soluble extract of pregnant m res urine containing natural conjugated estrogens in an amount constituting about 1% to about 30% of s id extract, and characterized in that the synthetic sodium estrone sulfate constitutes from about 10% to about of the total estrogen content of said composition.
• a composition comprising unstable crystalline synthetic sodium estrone sulfate stabilized by admixture with an extract of pregnant mares urine characterized in that said extract is water and alcohol-soluble and contains from about 5% to about 12% of natural conjugated estrogens; and that the synthetic sodium estrone sulfate constitutes from about 40% to about 75% of the total estrogen content of said composition.
• a composition comprising unstable crystalline synthetic sodium estrone sulfate stabilized by admixture with an extract of pregnant mares urine, said extract being characterized as being water and butanol-soluble and containing approximately 8% of natural conjugated estrogens; and the proportion of synthetic sodium estrone sulfate in said composition being approximately 65% of the total estrogen content.
• a composition comprising unstable crystalline synthetic sodium estrone sulfate stabilized by admixture With an extract of pregnant mares urine, said extract being characterized as being water and alcohol-soluble and containing approximately 10% of natural conjugated estro gens and the proportion of synthetic sodium estrone sulfate in said composition being approximately 60% of the total estrogen content.
• a composition comprising unstable crystalline synthetic sodium estrone sulfate stabilized by admixture with a pharmacologically-acceptaable carrier and a water and alcohol-soluble extract of pregnant mares urine con taining natural conjugated estrogens in an amount constituting about 1% to about 30% of said extract, and characterized in that the synthetic sodium estrone sulfate constitutes from about 10% to about 90% of the total estrogen content of said composition.
• a composition comprising unstable crystalline synthetic sodium estrone sulfate stabilized by admixture with a pharmacologically-acceptable carrier and an extract of pregnant mares urine characterized in that said extract is Water and alcohol-soluble and contains from about 5% to about 12% of natural conjugated estrogens; and that the synthetic sodium estrone sulfate constitutes from about 40% to about 75% of the total estrogen content of said composition.

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• Health & Medical Sciences (AREA)
• Chemical & Material Sciences (AREA)
• Life Sciences & Earth Sciences (AREA)
• General Health & Medical Sciences (AREA)
• Medicinal Chemistry (AREA)
• Pharmacology & Pharmacy (AREA)
• Epidemiology (AREA)
• Animal Behavior & Ethology (AREA)
• Public Health (AREA)
• Veterinary Medicine (AREA)
• Organic Chemistry (AREA)
• Cell Biology (AREA)
• Urology & Nephrology (AREA)
• Engineering & Computer Science (AREA)
• Biomedical Technology (AREA)
• Biotechnology (AREA)
• Developmental Biology & Embryology (AREA)
• Immunology (AREA)
• Virology (AREA)
• Zoology (AREA)
• Steroid Compounds (AREA)

Applications Claiming Priority (1)

Publications (1)

Family

ID=25092579

Family Applications (1)

Country Status (6)

Cited By (4)

• 1968
  • 1968-10-29 US US771668A patent/US3644618A/en not_active Expired - Lifetime
• 1969
  • 1969-11-27 NL NL6917875A patent/NL6917875A/xx not_active Application Discontinuation
  • 1969-12-02 BE BE742506D patent/BE742506A/xx unknown
  • 1969-12-02 DE DE19691960500 patent/DE1960500B2/de active Granted
  • 1969-12-02 GB GB58823/69A patent/GB1243308A/en not_active Expired
  • 1969-12-03 FR FR6941679A patent/FR2073252B1/fr not_active Expired

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